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Propargite, an environmental chemical, interacts with GWAS identified diabetes genes to impact human pancreatic β-cell death [propargite treatment]

ABSTRACT: This paper describes the first time a high-content environmental chemicals screen using pancreatic β-like cells derived from human pluripotent stem cells (hPSCs), and discovered that a commonly used pesticide, propargite, induces pancreatic β-cell DNA damage and necrosis. More interestingly, we found out the genetic background of β-like cells affects their response to propargite-induced toxicity, based on isogenic hPSC platform, including for variants GWAS identified associated with T1D, since isogenic GSTT1-/- and PTPN2-/- pancreatic β-like cells are hypersensitive to propargite-induced β-cell death both in vitro and in vivo. In summary, our study identified an environmental chemical that contributes to the loss of β-cells and provides an innovative platform for using hPSC-derived cells to explore gene-environment interactions that impact diabetes disease progression.

ORGANISM(S): Homo sapiens

PROVIDER: GSE83699 | GEO | 2018/07/01

REPOSITORIES: GEO

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Project description:A robust system using disease relevant cells to systematically evaluate the role in diabetes for loci identified through genome wide association studies (GWAS) is urgently needed. Toward this goal, we created isogenic mutant human embryonic stem cell (hESC) lines in GWAS-identified candidate diabetes genes including CDKAL1, KCNQ1 and KCNJ11, and used directed differentiation to evaluate the function of derivative human beta-like cells. The mutations did not affect the generation of insulin+ cells, but impaired insulin secretion both in vitro and in vivo, coinciding with defective glucose homeostasis. CDKAL1-/- insulin+ cells also displayed hypersensitivity to lipotoxicity. A high-content chemical screen identified a candidate drug that rescued CDKAL1-/--specific defects by inhibiting the AP1 (FOS/JUN) pathway. These studies establish a platform using isogenic hESCs to evaluate the function of GWAS-identified loci, and identify a drug candidate that rescues gene-specific defects, paving the way to precision therapy of metabolic diseases.A robust system using disease relevant cells to systematically evaluate the role in diabetes for loci identified through genome wide association studies (GWAS) is urgently needed. Toward this goal, we created isogenic mutant human embryonic stem cell (hESC) lines in GWAS-identified candidate diabetes genes including CDKAL1, KCNQ1 and KCNJ11, and used directed differentiation to evaluate the function of derivative human beta-like cells. The mutations did not affect the generation of insulin+ cells, but impaired insulin secretion both in vitro and in vivo, coinciding with defective glucose homeostasis. CDKAL1-/- insulin+ cells also displayed hypersensitivity to lipotoxicity. A high-content chemical screen identified a candidate drug that rescued CDKAL1-/--specific defects by inhibiting the AP1 (FOS/JUN) pathway. These studies establish a platform using isogenic hESCs to evaluate the function of GWAS-identified loci, and identify a drug candidate that rescues gene-specific defects, paving the way to precision therapy of metabolic diseases.

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Propargite, an environmental chemical, interacts with GWAS identified diabetes genes to impact human pancreatic β-cell death [propargite treatment]

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